Benzochromenones from the Marine Crinoid Comantheria rotula Inhibit Hypoxia-Inducible Factor-1(HIF-1)in Cell-Based Reporter Assays and Differentially Suppress the Growth of Certain Tumor Cell Lines

摘要

Hypoxia-inducible factor-1(HIF-1)is a transcription factor that promotes tumor cell adaptation and survival under hypoxic conditions.HIF-1 is currently recognized as an important molecular target for anticancer drag discovery.The National Cancer Institute open repository of marine invertebrates and algae lipid extracts was evaluated using a T47D breast tumor cell-based reporter assay for HIF-1 inhibitory activity.Bioassay-guided fractionation of an active extract from a crinoid Comantheria rotula yielded seven benzo[g]chromen-4-one and benzo[h]chromen-4-one pigments(1-7).The structures of the new benzo[g]chromenone dimer 9,9'-oxybis-neocomantherin(1)and another new natural pigment 5 were deduced from spectroscopic and spectrometric data.The crinoid pigments significantly inhibited both hypoxia-induced and iron chelator-induced HIF-1 luciferase reporter activity in breast and prostate tumor cells.However,inhibition of HIF-1 in the reporter assay did not translate into a significant decrease in the expression of the downstream HIF-1 target,secreted vascular endothelial growth factor(VEGF).Compound 1 was found to inhibit tumor cell growth in the NCI 60-cell line panel(GI50 values of 1.6-18.2 mu M),and compound 6 produced a unique pattern of tumor cell growth suppression.Five cell lines from different organs were hypersensitive to 6(GI50 values of 0.29-0.62 mu M),and three others were moderately sensitive(GI50 values of 2.2-5.1 mu M),while the GI50 values for most other cell lines ranged from 20 to 47 mu M.Crinoid benzo[g]chromenones were also found to scavenge radicals in a modified DPPH assay.